On September 22, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy drug nivolumab (Opdivo®) for some patients with advanced liver cancer (hepatocellular carcinoma). The approval covers the use of nivolumab in patients who have previously been treated with the targeted therapy sorafenib (Nexavar®).

The accelerated approval was based on results from the CheckMate-040 trial, which included patients with active hepatitis virus infection—the most common cause of liver cancer.

Despite the important role that hepatitis plays in the development of liver cancer, patients with active infection are usually excluded from clinical trials of new therapies for the disease, explained Renuka Iyer, M.D., co-director of the Liver and Pancreas Tumor Center at Roswell Park Cancer Institute in New York.

In the trial, about 19% of patients who had previously received sorafenib experienced either a complete response or partial response to nivolumab, and responses were seen in patients both with and without active hepatitis infection. In another subset of patients, tumors stopped growing during treatment.

Though the benefit of nivolumab was relatively modest overall, “we haven’t had anything give us this kind of response [in advanced liver cancer], so, to a liver doctor, this is a success,” said Dr. Iyer, who was not involved with the trial.

Early and Durable Treatment Response to Nivolumab

Sorafenib has been approved for the treatment of advanced liver cancer since 2007. The drug, part of a class of targeted therapies called tyrosine kinase inhibitors, is thought to work in part by blocking the formation of new blood vessels that tumors need to grow.

However, even with sorafenib treatment, the prognosis for advanced liver cancer has remained grim, with patients living less than 1 year on average.

Nivolumab, an immune checkpoint inhibitor, is already approved for the treatment of several other cancers, including melanoma, bladder cancer, head and neck cancer, and Hodgkin lymphoma.

Laboratory studies have shown that immune cells found within liver tumors often overexpress the protein targeted by nivolumab, called PD-1, which prevents those immune cells from recognizing and attacking the cancer cells.

Those findings led researchers to begin testing drugs like nivolumab to determine whether they might benefit patients with liver cancer.

The CheckMate-040 trial enrolled 262 patients with advanced liver cancer. The accelerated approval was based on a subset of 154 patients in the trial whose disease had gotten worse during treatment with sorafenib or who could not take sorafenib because of side effects. Of these, 31% had an active hepatitis B infection and 21% had an active hepatitis C infection.

Out of the 154 patients who had previously received sorafenib, three had a complete response to nivolumab and 19 had a partial response. One of the complete responses was seen in a patient with active hepatitis B infection. In addition, tumors stopped growing—known as stable disease—for at least 6 months in 40% of patients.

In a pattern similar to that seen with the use of nivolumab in other cancer types (including colorectal cancer), the responses occurred early in treatment and persisted for long periods: 91% of responses lasted for 6 months or longer and 55% lasted for a year or more.

Serious side effects seen in the trial included elevation of liver enzyme levels, indicating possible liver damage, and liver inflammation caused by an immune system reaction. There were no treatment-related deaths during the trial.

Reversing Immune Cell Dysfunction

Immunotherapies in general are promising for liver cancer, explained Dr. Iyer, because “immune dysfunction exists in [liver] cancer for a variety of reasons—one of the big reasons being hepatitis itself.”

Cirrhosis, another cause of liver cancer, can also cause inflammation and prevent the immune system from targeting cancer cells.

“It’s possible that [nivolumab] is reversing some of this dysfunction, allowing the immune system to recognize the tumor and [produce] these sustained and durable responses that we’re seeing,” said Dr. Iyer.

After a decade with little progress in liver cancer treatment, nivolumab’s approval marks the second for the disease this year, noted Tim Greten, M.D., of the Thoracic and Gastrointestinal Oncology Branch in NCI’s Center for Cancer Research.

The nivolumab approval is notable, Dr. Greten continued, because it “utilizes a very different mechanism” than tyrosine kinase inhibitors. But, he continued, “more studies are needed to understand why a relatively small percentage of patients respond to nivolumab.”

Researchers are already looking for ways to increase responses to the drug, Dr. Iyer said. These include testing nivolumab in combination with other therapies, including with other immunotherapy drugs and with sorafenib.

Other research teams are looking at whether giving radiation therapy before immunotherapy can cause liver tumor cells to produce antigens that may allow the immune system to better recognize the tumors, she added.

Under accelerated approvals, companies are required to conduct larger studies to confirm that the therapy improves patient outcomes. Bristol-Myers Squibb, which manufactures nivolumab, is sponsoring a phase 3, randomized clinical trial—CheckMate-459—which is comparing nivolumab against sorafenib as an initial treatment for patients with advanced liver cancer.

For patients with advanced liver cancer, having new immunotherapy options “is truly exciting,” Dr. Iyer said. “Until now, we had just one class of drugs, and this [approval] really opens the door and gives them hope.”

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